Lipidomic analysis of Toxoplasma gondii tachyzoites rhoptries: further insights into the role of cholesterol.
Rhoptries are secretory organelles involved in the virulence of the human pathogen Toxoplasma gondii. In the present study we have used HPLC and capillary GLC to isolate and quantify lipids from whole Toxoplasma cells and their purified rhoptries. This comparative lipidomic analysis revealed an enrichment of cholesterol, sphingomyelin and, most of all, saturated fatty acids in the rhoptries. These lipids are known, when present in membranes, to contribute to their rigidity and, interestingly, fluorescence anisotropy measurements confirmed that rhoptry-derived membranes have a lower fluidity than membranes from whole T. gondii cells. Moreover, although rhoptries were initially thought to be highly enriched in cholesterol, we demonstrated that cholesterol is present in lower proportions, and we have provided additional evidence towards a lack of involvement of rhoptry cholesterol in the process of host-cell invasion by the parasite. Indeed, depleting the cholesterol content of the parasites did not prevent the secretion of protein-containing rhoptry-derived vesicles and the parasites could still establish a structure called the moving junction, which is necessary for invasion. Instead, the crucial role of host cholesterol for invasion, which has already been demonstrated [Coppens and Joiner (2003) Mol. Biol. Cell 14, 3804-3820], might be explained by the need of a cholesterol-rich region of the host cell we could visualize at the point of contact with the attached parasite, in conditions where parasite motility was blocked.


Echocardiographic reference ranges for normal left atrial function parameters: results from the EACVI NORRE study.
To obtain the normal ranges for echocardiographic measurements of left atrial (LA) function from a large group of healthy volunteers accounting for age and gender. A total of 371 (median age 45 years) healthy subjects were enrolled at 22 collaborating institutions collaborating in the Normal Reference Ranges for Echocardiography (NORRE) study of the European Association of Cardiovascular Imaging (EACVI). Left atrial data sets were analysed with a vendor-independent software (VIS) package allowing homogeneous measurements irrespective of the echocardiographic equipment used to acquire data sets. The lowest expected values of LA function were 26.1%, 48.7%, and 41.4% for left atrial strain (LAS), 2D left atrial emptying fraction (LAEF), and 3D LAEF (reservoir function); 7.7%, 24.2%, and -0.53/s for LAS-active, LAEF-active, and LA strain rate during LA contraction (SRa) (pump function) and 12.0% and 21.6% for LAS-passive and LAEF-passive (conduit function). Left atrial reservoir and conduit function were decreased with age while pump function was increased. All indices of reservoir function and all LA strains had no difference in both gender and vendor. However, inter-vendor differences were observed in LA SRa despite the use of VIS. The NORRE study provides contemporary, applicable echocardiographic reference ranges for LA function. Our data highlight the importance of age-specific reference values for LA functions.


Index for the evaluation of the general photometric performance of photometers.
The General V(λ) Mismatch Index, f1 ', was defined for a general description of the photometric performance of photometers. This index is widely-used in photometry, and it is very relevant for selecting photometers for low-uncertainty photometric measurements. It quantifies the spectral mismatch between the relative spectral responsivity of a photometer and the luminous efficiency function for photopic vision, V(λ). The linear correlation between the real general photometric measurement error and f1 ' of 77 photometers was studied for four sets of light sources: R, G and B LEDs (narrowband spectral power distributions, SPDs), blackbodies at different colour temperatures (broadband SPDs), phosphor-based LEDs at different correlated color temperatures (SPDs with narrow- and broad-band features), and a mixture of blackbodies and phosphor-based LED sources. This article shows that it can be defined an alternative index which is notably better correlated with the real general photometric measurement error of the photometers under light sources with broadband features in their SPDs, adequate for general lighting. This index is based on filtering the high spectral frequencies variations between the relative spectral responsivity of the photometer and V(λ). The use of this new index for the assessment of the general photometric performance of photometers would improve the selection of high quality photometers and, consequently, would contribute to the general improvement of photometric measurements.


AWclust: point-and-click software for non-parametric population structure analysis.
Population structure analysis is important to genetic association studies and evolutionary investigations. Parametric approaches, e.g. STRUCTURE and L-POP, usually assume Hardy-Weinberg equilibrium (HWE) and linkage equilibrium among loci in sample population individuals. However, the assumptions may not hold and allele frequency estimation may not be accurate in some data sets. The improved version of STRUCTURE (version 2.1) can incorporate linkage information among loci but is still sensitive to high background linkage disequilibrium. Nowadays, large-scale single nucleotide polymorphisms (SNPs) are becoming popular in genetic studies. Therefore, it is imperative to have software that makes full use of these genetic data to generate inference even when model assumptions do not hold or allele frequency estimation suffers from high variation. We have developed point-and-click software for non-parametric population structure analysis distributed as an R package. The software takes advantage of the large number of SNPs available to categorize individuals into ethnically similar clusters and it does not require assumptions about population models. Nor does it estimate allele frequencies. Moreover, this software can also infer the optimal number of populations. Our software tool employs non-parametric approaches to assign individuals to clusters using SNPs. It provides efficient computation and an intuitive way for researchers to explore ethnic relationships among individuals. It can be complementary to parametric approaches in population structure analysis.


The utility of glomerular C4d immunostaining in renal biopsies in patients with immunoglobulin A nephropathy. A clinicopathological study.
The course of IgA nephropathy (IgAN) is highly variable and ranges from a totally benign condition to end-stage renal disease in approximately one third of cases. The identification of new prognostic markers could provide insights into the pathogenesis of IgAN and unveil new therapeutic avenues. Glomerular deposition of C4d is a marker of activation of the lectin pathway of complement. It is thought that activation of the lectin pathway in IgAN is associated with more severe renal damage, and more severe histological findings. In view of the above, the aim of the present study was to compare the clinical presentation, laboratory data, and histological lesions in the renal biopsy in IgAN patients with positive and negative staining for mesangial C4d depositions. Our study revealed that hypertension, severe proteinuria, a high level of serum creatinine, low eGFR at the time of presentation, as well as tubular atrophy/interstitial fibrosis > 50%, and endocapillary proliferation were significantly more frequent in the C4d (+) group than in the C4d (-) group. Based on our research, we can assume that mesangial immunoexpression of C4d seems to be a useful prognostic factor in IgAN.


Clinical efficacy and safety of percutaneous drainage for post-operative fluid collection in patients with bladder cancer undergoing radical cystectomy and urinary diversion.
To evaluate the success rates of percutaneous drainage for fluid collection after radical cystectomy, with emphasis on factors affecting the clinical success, including lesion, patient, and procedure characteristics. In this retrospective study, 31 percutaneous drainage catheters were placed in 29 consecutive patients between January 2021 and September 2023. Most fluid collections formed near the uretero-ileal anastomosis site in the right pelvic cavity (80.6%). The technical success rate was 100%. The primary and final clinical success was 80.6% and 96.9%, respectively. Lymphoceles notably increased the primary clinical failure risk (odds ratio and 95% confidential interval: 22.667 (1.839-279.366), P = .015). Significant differences were observed between transabdominal and transgluteal approaches in terms of fluoroscopic time, dose, and location. Leakage indications on computed tomography prompted differing interventions, but all achieved final clinical success. Percutaneous drainage for post-operative fluid collection is safe and effective in patients with radical cystectomy and urinary diversion.


Single Nucleotide Polymorphisms: A Window into the Informatics of the Living Genome.
Nested in the environment of the nucleus of the cell, the 23 sets of chromosomes that comprise the human genome function as one integrated whole system, orchestrating the expression of thousands of genes underlying the biological characteristics of the cell, individual and the species. The extraction of meaningful information from this complex data set depends crucially upon the lens through which the data are examined. We present a biophysical perspective on genomic information encoded in single nucleotide polymorphisms (SNPs), and introduce metrics for modeling information encoded in the genome. Information, like energy, is considered to be a conserved physical property of the universe. The information structured in SNPs describes the adaptation of a human population to a given environment. The maintained order measured by the information content is associated with entropies, energies, and other state variables for a dynamic system in homeostasis. "Genodynamics" characterizes the state variables for genomic populations that are stable under stochastic environmental stresses. The determination of allelic energies allows the parameterization of specific environmental influences upon individual alleles across populations. The environment drives population-based genome variation. From this vantage point, the genome is modeled as a complex, dynamic information system defined by patterns of SNP alleles and SNP haplotypes.


[Our results of surgical management of unstable pelvic ring injuries].
The authors present a group of patients treated for pelvic fractures in a period of 6 years and they evaluate radiographic findings and clinical outcomes following surgical management of type B and type C fractures. Between July 1998 and June 2004, a total of 271 patients with pelvic fractures, 162 men and 109 women (average age, 42 years; range, 15 to 93 years) were hospitalized at the authors' departments. Of these, 141 patients were operated on (94 men, 47 women; average age, 37 years; range, 15 to 72 years) and 130 were treated conservatively (average age, 47 years; range, 15 to 93 years). The clinical outcome assessment in patients with type B and type C fractures treated surgically was based on the Majeed scoring system, and the radiographs were evaluated as described by Matta and Tornetta. In 85 % of the patients, pelvic fractures were due to a high-energy trauma caused by traffic accidents in 63 % (pedestrian injury, 30 %; injury of the driver or passenger, 28 %; motorcycle injury, 5 %), by falls from heights in 20 % (occupational injury, 10 %; suicidal attempt, 10 %) and by other causes in 2 %. Sports accidents, usually due to a low-energy trauma, accounted for 8 % of the injuries (falls from a bicycle, violent kicks) and ordinary falls of elderly persons for 7 %. Type A injury was in 56 patients (21 %), type B in 103 patients (38 %) and type C in 112 patients (41 %). In 27 % of the patients, pelvic ring injury was part of a multiple trauma, in 58 % it was a combined injury and in 15 % it presented as a single trauma. Primary neurological deficit was found in nine patients (9 %) with type B fracture and in 20 patients (18 %) with type C fracture; this difference was statistically significant (p = 0.005). Urogenital injury was co-existent with type B fracture in 12 patients (12 %) and with type C fracture in 15 patients (13 %); the difference was not significant (p = 0.734). In seven patients (3 %), the injury involved an open fracture. Thirty-three patients (12 %) died during hospitalization. The difference in death rate between the patients with type C and those with type B fractures was significant (p = 0.021). Excellent and good clinical outcomes were achieved in 83 % and 70 % of the patients with type B and type C fractures, respectively. The difference was not significant (p = 0.236). Radiographs showed excellent reduction in 83 % of type B fractures and in 61 % of type C fractures; the difference was not significant (p = 0.271). Intra-operative complications were recorded in 22 %, early post-operative ones in 13 % and late complications in 11 % of the patients. The significant difference in primary neurological deficit between the patients with type C fractures and those with type B fractures was attributed to more severe injury and vertical dislocation of the posterior segment in type C fractures. On the other hand, the fact that urogenital involvement was not significantly higher in type C fractures can be explained by an equal presence of anterior segment injury in both type B and type C fractures. The significantly higher number of deaths in patients with type C fractures, as compared with those with type B fractures, was related more to severe injuries of other organ systems in polytraumatized patients than to injuries of the pelvis itself, although severe injury to the posterior segment in type C fractures can result in massive bleeding into the retroperitoneum. An active approach to the treatment of patients with unstable pelvic fractures, which is based on the correct diagnosis, comprehensive multi-disciplinary care, urgent primary stabilization and early definitive fixation by internal osteosynthesis, offers a prospect of survival and a good functional outcome for the patient. However, a high proportion of lasting sequelae due to altered biomechanics of the pelvic ring, and irreversible injuries to neural structures and the urogenital system may lessen good results achieved by a demanding surgical procedure on the skeleton.


Role of Monocytes in the Pathogenesis of Dengue.
Diseases caused by dengue virus (DENV) are a major public health problem worldwide, considered one of the infections with more prevalence in tropical and subtropical zones of the world. Despite the intense research in the pathogenesis of DENV, this feature is not well understood. One of the main target cells for DENV infection is monocytes; these phagocytes can play a dual role, since they are essential to control viremia, but they also participate in the induction of tissue damage during DENV infection. Monocytes produce different pro-inflammatory cytokines and chemokines in response to infection, and also mediate endothelial damage. In peripheral blood, monocytes can be divided into three different subpopulations, namely classical, intermediate and non-classical, which differ in frequency, cytokine production, among others. Studies in the last years suggest that non-classical monocytes have higher affinity for microvasculature endothelium compared to other type of monocytes, which implies that they could be more involved in the increase of endothelial permeability observed during DENV infection. This review provides a general view of the role of monocytes and their subpopulations in DENV pathogenesis and its effect in viral replication. Finally, the potential contribution of these phagocytes in the alterations of endothelial permeability is discussed.


Wearable Electrochemical Sensors in Parkinson's Disease.
Parkinson's disease (PD) is a neurodegenerative disorder associated with widespread aggregation of α-synuclein and dopaminergic neuronal loss in the substantia nigra pars compacta. As a result, striatal dopaminergic denervation leads to functional changes in the cortico-basal-ganglia-thalamo-cortical loop, which in turn cause most of the parkinsonian signs and symptoms. Despite tremendous advances in the field in the last two decades, the overall management (i.e., diagnosis and follow-up) of patients with PD remains largely based on clinical procedures. Accordingly, a relevant advance in the field would require the development of innovative biomarkers for PD. Recently, the development of miniaturized electrochemical sensors has opened new opportunities in the clinical management of PD thanks to wearable devices able to detect specific biological molecules from various body fluids. We here first summarize the main wearable electrochemical technologies currently available and their possible use as medical devices. Then, we critically discuss the possible strengths and weaknesses of wearable electrochemical devices in the management of chronic diseases including PD. Finally, we speculate about possible future applications of wearable electrochemical sensors in PD, such as the attractive opportunity for personalized closed-loop therapeutic approaches.


Computer generated holography using parallel commodity graphics hardware.
This paper presents a novel method for using programmable graphics hardware to generate fringe patterns for SLM-based holographic displays. The algorithm is designed to take the programming constraints imposed by the graphics hardware pipeline model into consideration, and scales linearly with the number of object points. In contrast to previous methods we do not have to use the Fresnel approximation. The technique can also be used on several graphics processors in parallel for further optimization. We achieve real-time frame rates for objects consisting of a few hundred points at a resolution of 960x600 pixels and over 10 frames per second for 1000 points.


Hepatic Choline Transport Is Inhibited During Fatty Acid-Induced Lipotoxicity and Obesity.
Choline is an essential nutrient and a critical component of the membrane phospholipid phosphatidylcholine (PC), the neurotransmitter acetylcholine, while also contributing to the methylation pathway. In the liver specifically, PC is the major membrane constituent and can be synthesized by the cytidine diphosphate-choline or the phosphatidylethanolamine N-methyltransferase pathway. With the continuing global rise in the rates of obesity and nonalcoholic fatty liver disease, we sought to explore how excess fatty acids on primary hepatocytes and diet-induced obesity affect choline uptake and metabolism. Our results demonstrate that hepatocytes chronically treated with palmitate, but not oleate or a mixture, had decreased choline uptake, which was associated with lower choline incorporation into PC and lower expression of choline transport proteins. Interestingly, a reduction in the rate of degradation spared PC levels in response to palmitate when compared with control. The effects of palmitate treatment were independent of endoplasmic reticulum stress, which counterintuitively augmented choline transport and transporter expression. In a model of obesity-induced hepatic steatosis, male mice fed a 60% high-fat diet for 10 weeks had significantly diminished hepatic choline uptake compared with lean mice fed a control diet. Although the transcript and protein expression of various choline metabolic enzymes fluctuated slightly, we observed reduced protein expression of choline transporter-like 1 (CTL1) in the liver of mice fed a high-fat diet. Polysome profile analyses revealed that in livers of obese mice, the CTL1 transcript, despite being more abundant, was translated to a lesser extent compared with lean controls. Finally, human liver cells demonstrated a similar response to palmitate treatment. Conclusion: Our results suggest that the altered fatty acid milieu seen in obesity-induced fatty liver disease progression may adversely affect choline metabolism, potentially through CTL1, but that compensatory mechanisms work to maintain phospholipid homeostasis.


Dedifferentiated Liposarcoma With Epithelioid/Epithelial Features.
Dedifferentiated liposarcoma (DDLPS) demonstrates a variety of growth patterns, and their histologic resemblance to other spindle cell mesenchymal tumors has been widely recognized. However, epithelioid morphology in DDLPS has only rarely been documented. Here, we report 6 cases of DDLPS with striking epithelioid/epithelial features. The patients were 5 men and 1 woman with a median age of 61 years. All tumors were located in the internal trunk. During follow-up of 1 to 41 months, local recurrence, distant metastases, and tumor-related death occurred in 4, 2, and 4 patients, respectively. Beside well-differentiated liposarcoma component and conventional high-grade spindle cell morphology, all tumors focally exhibited growth comprising small or large epithelioid cells in diffuse or sheet-like proliferation. Rhabdoid cells were present in 2 cases. All 5 tumors tested harbored MDM2 amplification. Cytokeratin and/or epithelial membrane antigen were at least focally positive in all 5 tumors tested. One case contained a small focus of novel heterologous epithelial differentiation with acinar structures, wherein cytokeratin, MOC31, and claudin-4 were diffusely expressed and H3K27me3 expression was lost. DDLPS with epithelioid/epithelial features may lead to misdiagnosis of carcinoma or mesothelioma, and their diagnosis should be based on correlation with clinicopathologic and molecular findings. The epithelioid morphology in DDLPS may suggest an aggressive behavior based on this small series. In addition, we document 2 cases of MDM2-amplified undifferentiated neoplasm with epithelioid features in the internal trunk that lacked association with well-differentiated liposarcoma histology and showed rapid clinical course. Whether these latter tumors belong to DDLPS with epithelioid features requires further study.


The influence of masting phenomenon on growth-climate relationships in trees: explaining the influence of previous summers' climate on ring width.
Tree growth is frequently linked to weather conditions prior to the growing season but our understanding of these lagged climate signatures is still poorly developed. We investigated the influence of masting behaviour on the relationship between growth and climate in European Beech (Fagus sylvatica L.) using a rare long-term dataset of seed production and a new regional tree ring chronology. Fagus sylvatica is a masting species with synchronous variations in seed production which are strongly linked to the temperature in the previous two summers. We noted that the weather conditions associated with years of heavy seed production (mast years) were the same as commonly reported correlations between growth and climate for this species. We tested the hypothesis that a trade-off between growth and reproduction in mast years could be responsible for the observed lagged correlations between growth and previous summers' temperatures. We developed statistical models of growth based on monthly climate variables, and show that summer drought (negative correlation), temperature of the previous summer (negative) and temperature of the summer 2 years previous (positive) are significant predictors of growth. Replacing previous summers' temperature in the model with annual seed production resulted in a model with the same predictive power, explaining the same variance in growth. Masting is a common behaviour in many tree species and these findings therefore have important implications for the interpretation of general climate-growth relationships. Lagged correlations can be the result of processes occurring in the year of growth (that are determined by conditions in previous years), obviating or reducing the need for 'carry-over' processes such as carbohydrate depletion to be invoked to explain this climate signature in tree rings. Masting occurs in many tree species and these findings therefore have important implications for the interpretation of general climate-growth relationships.


The Distally Based Peroneus Brevis Flap: The 5-Step Technique.
The peroneus brevis flap was first described as proximally based by Mathes et al (Surg Clin North Am. 1974;54:1337-1354) and later by Jackson and Scheker (Injury. 1982;13:324-330). A distally based version of this flap by Mathes and Nahai (Reconstructive Surgery: Principles, Anatomy and Technique. 1997:1437e46) was subsequently described in 1997. The first case series of distally based flaps was published by Eren et al (Plast Reconstr Surg. 2001;107:1443-1448). In our experience, the distally based flap is a useful muscle flap to reconstruct small defects in the lateral distal third of the leg. Initial interest and confidence in the use of this flap in our unit were hindered by lack of direct experience and descriptive detail in the literature. We have now developed a systematic approach to harvest the distally pedicled peroneus brevis muscle flap in 5 reproducible, safe steps. This has allowed the flap to become adopted as a standard technique of limb reconstruction in our unit with no cases of flap loss.


Berg balance scale: intrarater test-retest reliability among older people dependent in activities of daily living and living in residential care facilities.
The Berg Balance Scale (BBS) is frequently used to assess balance in older people, but knowledge is lacking about the absolute reliability of BBS scores. The aim of this study was to investigate the absolute and relative intrarater test-retest reliability of data obtained with the BBS when it is used among older people who are dependent in activities of daily living and living in residential care facilities. The participants were 45 older people (36 women and 9 men) who were living in 3 residential care facilities. Their mean age was 82.3 years (SD=6.6, range=68-96), and their mean score on the Mini Mental State Examination was 17.5 (SD=6.3, range=4-30). The BBS was assessed twice by the same assessor. The intrarater test-retest reliability assessments were made at approximately the same time of day and with 1 to 3 days in between assessments. Absolute reliability was calculated using an analysis of variance with a 95% confidence level, as suggested by Bland and Altman. Relative reliability was calculated using the intraclass correlation coefficient (ICC). The mean score was 30.1 points (SD=15.9, range=3-53) for the first BBS test and 30.6 points (SD=15.6, range=4-54) for the retest. The mean absolute difference between the 2 tests was 2.8 points (SD=2.7, range=0-11). The absolute reliability was calculated as being 7.7 points, and the ICC was calculated to .97. Despite a high ICC value, the absolute reliability showed that a change of 8 BBS points is required to reveal a genuine change in function among older people who are dependent in activities of daily living and living in residential care facilities. This knowledge is important in the clinical setting when evaluating an individual's change in balance function over time in this group of older people.


Evolutionary rate analyses of orthologs and paralogs from 12 Drosophila genomes.
The newly sequenced genome sequences of 11 Drosophila species provide the first opportunity to investigate variations in evolutionary rates across a clade of closely related species. Protein-coding genes were predicted using established Drosophila melanogaster genes as templates, with recovery rates ranging from 81%-97% depending on species divergence and on genome assembly quality. Orthology and paralogy assignments were shown to be self-consistent among the different Drosophila species and to be consistent with regions of conserved gene order (synteny blocks). Next, we investigated the rates of diversification among these species' gene repertoires with respect to amino acid substitutions and to gene duplications. Constraints on amino acid sequences appear to have been most pronounced on D. ananassae and least pronounced on D. simulans and D. erecta terminal lineages. Codons predicted to have been subject to positive selection were found to be significantly over-represented among genes with roles in immune response and RNA metabolism, with the latter category including each subunit of the Dicer-2/r2d2 heterodimer. The vast majority of gene duplications (96.5%) and synteny rearrangements were found to occur, as expected, within single Müller elements. We show that the rate of ancient gene duplications was relatively uniform. However, gene duplications in terminal lineages are strongly skewed toward very recent events, consistent with either a rapid-birth and rapid-death model or the presence of large proportions of copy number variable genes in these Drosophila populations. Duplications were significantly more frequent among trypsin-like proteases and DM8 putative lipid-binding domain proteins.


Labour market attachment dynamics in patients with concussion: a Danish nationwide register-based cohort study.
Concussion may lead to persisting post-concussive symptoms affecting work ability and employment. This study examined the transitions between labour market states an individual can experience after the acute phase of concussion. The aim was to describe the incidence of favourable and adverse transitions between different labour market states (e.g., employment, sick leave) in relation to socioeconomic and health characteristics in individuals with concussion relative to matched controls. This Danish nationwide register-based cohort study extracted 18-60-year-old individuals between 2003-2007 with concussion from the Danish National Patient Register (ICD-10 S06.0). Controls were matched on age, sex, and municipality. Patients and controls were followed for 5 years starting three months after injury. Exclusion criteria were neurological injuries and unavailability to the labour market in the inclusion period (2003-2007) and 5-years before injury (1998-2002). Labour market states were defined from transfer income data in the Danish Register for Evaluation of Marginalization. Incidence rates of transitions between these labour market states were analysed in multistate models. Transitions were bundled in favourable and adverse transitions between labour market states and the difference in incidence rates between individuals with concussion relative to matched controls were assessed with hazard ratios from Cox regression models. Persons with concussion (n = 15.580) had a lower incidence of favourable transitions (HR 0.88, CI 0.86-0.90) and a higher incidence of adverse transitions (HR 1.30, CI 1.27-1.35), relative to matched controls (n = 16.377). The effect of concussion differed depending on health and socioeconomic characteristics. Notably, individuals between 30-39 years (HR 0.83, CI 0.79-0.87), individuals with high-income (200.000-300.000 DKK) (HR 0.83, CI 0.80-0.87), and wage earners with management experience (HR 0.60, CI 0.44-0.81) had a markedly lower incidence of favourable transitions compared to controls. Additionally, individuals with high income also had a higher incidence of adverse transitions (HR 1.46, CI 1.34-1.58) compared to controls. Concussion was associated with enhanced risk of adverse transitions between labour market states and lower occurrence of favourable transitions, indicating work disability, potentially due to persistent post-concussive symptoms. Some age groups, individuals with high income, and employees with management experience may be more affected.


Complications of fluoroscopically guided extraforaminal cervical nerve blocks. An analysis of 1036 injections.
A number of serious complications associated with fluoroscopically guided extraforaminal cervical nerve blocks have been reported in the literature. The purpose of the present study was to determine the rate of complications associated with these blocks and to determine whether needle positioning during the procedure affected the prevalence of complications at one institution. Between October 1999 and June 2003, we performed 1036 fluoroscopically guided extraforaminal cervical nerve blocks in 844 patients. Plain radiographs documenting the procedure were made as part of the standard quality-assurance protocol. An independent observer who was uninvolved with the procedures reviewed a prospectively kept database on all patients. We subsequently reviewed the patient records to identify complications. There were no catastrophic complications such as vessel damage, paralysis, or death. Overall, fourteen patients (1.66%) had a minor complication in association with the procedure. With the numbers available, the rate of complications associated with pdeep injection (798 blocks) was not significantly different from that associated with shallow injection (238 blocks) (1.89% compared with 0.84%). However, the rate of complications associated with anterior placement of the needle tip (thirty-three blocks) was higher than that associated with ideal placement of the needle tip (904 blocks) (6.06% compared with 1.55%) (p = 0.04). No catastrophic complications occurred in this series of 1036 nerve blocks. We found that the medial-lateral needle depth as seen on frontal-view radiographs was not associated with complications, although the anterior positioning of the needle as seen on lateral-view radiographs was associated with minor complications. Our results suggest that, with our technique, cervical nerve blocks are relatively safe procedures.


A time-comparison circuit in the electric fish midbrain. I. Behavior and physiology.
Behavioral experiments show that the weakly electric fish, Eigenmannia, detects differences in timing as small as 400 nsec between electric signals from different parts of its body surface. The neural basis of this remarkable temporal resolution was investigated by recording from elements of the phase-coding system, a chain of electrotonically connected neurons devoted to the processing of temporal information. Each element of this system fires a single action potential for every cycle of the electric signal (either the fish's own electric organ discharge or a sinusoidal signal of similar frequency). For phase-coding primary afferents and midbrain neurons, the temporal resolution was determined by measuring each unit's capacity to lock its spike to a particular phase of the stimulus cycle. The jitter of a neuron's response (measured as the standard deviation of the timing of the spikes with respect to the stimulus) decreases from the level of the primary afferent (mean = 30 microsec) to the midbrain torus (mean = 11 microsec); these results can be correlated with morphological measures of convergence. The temporal resolution of single neurons is still inferior to that displayed at the behavioral level.


In silico strain optimization by adding reactions to metabolic models.
Nowadays, the concerns about the environment and the needs to increase the productivity at low costs, demand for the search of new ways to produce compounds with industrial interest. Based on the increasing knowledge of biological processes, through genome sequencing projects, and high-throughput experimental techniques as well as the available computational tools, the use of microorganisms has been considered as an approach to produce desirable compounds. However, this usually requires to manipulate these organisms by genetic engineering and/ or changing the enviromental conditions to make the production of these compounds possible. In many cases, it is necessary to enrich the genetic material of those microbes with hereologous pathways from other species and consequently adding the potential to produce novel compounds. This paper introduces a new plug-in for the OptFlux Metabolic Engineering platform, aimed at finding suitable sets of reactions to add to the genomes of selected microbes (wild type strain), as well as finding complementary sets of deletions, so that the mutant becomes able to overproduce compounds with industrial interest, while preserving their viability. The necessity of adding reactions to the metabolic model arises from existing gaps in the original model or motivated by the productions of new compounds by the organism. The optimization methods used are metaheuristics such as Evolutionary Algorithms and Simulated Annealing. The usefulness of this plug-in is demonstrated by a case study, regarding the production of vanillin by the bacterium E. coli.


Experimental illumination of a fitness landscape.
The genes of all organisms have been shaped by selective pressures. The relationship between gene sequence and fitness has tremendous implications for understanding both evolutionary processes and functional constraints on the encoded proteins. Here, we have exploited deep sequencing technology to experimentally determine the fitness of all possible individual point mutants under controlled conditions for a nine-amino acid region of Hsp90. Over the past five decades, limited glimpses into the relationship between gene sequence and function have sparked a long debate regarding the distribution, relative proportion, and evolutionary significance of deleterious, neutral, and advantageous mutations. Our systematic experimental measurement of fitness effects of Hsp90 mutants in yeast, evaluated in the light of existing population genetic theory, are remarkably consistent with a nearly neutral model of molecular evolution.


Hierarchies of loss: a critique of disenfranchised grief.
Two aspects of the concept of disenfranchised grief are examined: its binary assumption that grief is either enfranchised or disenfranchised; and its emancipatory agenda that grief should not be socially regulated. Focusing on the mourner's relationship to the deceased, we argue that social norms about the legitimacy of bereavement are not binary (yes-no), but are scalar or hierarchical, or even more complex still. We report on a tool for identifying hierarchies of loss, and describe the hierarchy identified by this tool in one British study. If norms about loss are not binary but hierarchical, how has disenfranchised grief--which claims to be a theory of norms--become an uncontested concept within bereavement research and clinical practice? We point to its rhetorical value in the postmodern politics of grief and its seductive emancipatory symbolism within the clinic; its value both for clinical practice and for empirical research into bereavement norms, however, may be limited.


Exploring Refinement Strategies for Single Housing of Male C57BL/6JRj Mice: Effect of Cage Divider on Stress-Related Behavior and Hypothalamic-Pituitary-Adrenal-Axis Activity.
Introduction: Single housing of laboratory mice is a common practice to meet experimental needs, or to avoid intermale aggression. However, single housing is considered to negatively affect animal welfare and may compromise the scientific validity of experiments. The aim of this study was to investigate whether the use of a cage with a cage divider, which avoids physical contact between mice while maintaining sensory contact, may be a potential refinement strategy for experiments in which group housing of mice is not possible. Methods: Eight-week-old male C57BL/6JRj mice were single housed, pair housed or pair housed with a cage divider for four (experiment 1) or ten (experiment 2) weeks, after which we performed an open field test, Y-maze spontaneous alternation test, elevated plus maze test, an auditory fear conditioning task, and assessed responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis. Results: Housing conditions did not affect body weight, exploratory activity, anxiety, working memory, fear memory processing or markers for HPA-axis functioning in either experiment 1 or experiment 2. There was an increased distance traveled in mice housed with a cage divider compared to pair housed mice after 4 weeks, and after 10 weeks mice housed with a cage divider made significantly more arm entries in the Y-maze spontaneous alternation test. Conclusion: Taken together, our study did not provide evidence for robust differences in exploratory activity, anxiety, working memory and fear memory processing in male C57BL/6JRj mice that were single housed, pair housed or pair housed with a cage divider.


Transmission modeling and health systems: the case of TB in India.
TB in India presents the challenges of a complex disease in a complex healthcare system. Mathematical models, offering a framework for capturing such complexities, have proven useful in exploring strategies for the control of TB. As the use of such techniques develops in future, it is important to understand what aspects of the healthcare system are most critical for models to faithfully capture. We ask what type of intervention should be prioritized for the control of TB, amongst: improved diagnosis of TB per visit to a healthcare provider; improved treatment success; and increased identification of TB cases in the community? Using simple mathematical models, calibrated to the national TB epidemic in India, we explore how the relative importance of each of these interventions is affected by different assumptions for the patient pathway in careseeking, thus outlining aspects of the healthcare system that may matter most for the transmission dynamics of TB. We illustrate that, under a range of plausible parameter assumptions, it is possible to generate conditions under which a case-finding intervention would be prioritized over improvement of diagnosis and treatment, and vice versa. Key data needs include: the proportion of patients not contacting the healthcare system, and the mean patient delay before first seeking care. For mathematical models addressing strategic priorities for TB control, it is important to adequately quantify the dynamics of careseeking. We outline ways in which these data gaps may be addressed, and questions for future work.


[Imaging of bronchogenic cysts].
Bronchogenic cysts, unlike the other mediastinal cysts, exhibit a high incidence of complications, which makes their resection advisable even if no symptoms are present. The correct diagnosis should thus be made with the available imaging modalities. We reviewed our series of 11 bronchogenic cysts, all of them studied with conventional radiology (CR), as well as with such newer imaging modalities as CT and/or MRI. All mediastinal lesions had fluid density at CT and were homogeneously hyperintense on T2-weighted MR images. On the contrary, on T1-weighted images, some lesions were hypointense and some hyperintense, probably because of their rich protein content. In contrast, hilar or pulmonary lesions had air inside, except for one case--characterized by multiple localizations--in which the hilar lesion exhibited the same fluid density as the mediastinal lesions. The CT or MR finding of a lesion with fluid content below the carina permits a nearly unquestionable diagnosis of bronchogenic cyst since the other cystic lesions involve this region very rarely. In all the other cases, other types of mediastinal or hilar-pulmonary lesions cannot be ruled out. In particular, in case of cysts in paraesophageal site, no imaging modality permits to differentiate bronchogenic from enteric cysts; in some cases, the differential diagnosis may be impossible even with histology of the resected specimen.


Physician revalidation in Europe.
Despite the increasing attention on patient mobility, there remains a lack of European-level interest in assuring the sustained competence of health professionals. Specifically, the existing European legal framework fails to recognise the introduction of periodic revalidation and requirements to participate in continuing professional development in some countries. This study shows that the definitions and mechanisms of revalidation vary significantly across member states. While some countries, eg Austria, Germany and Spain, look to continuing medical education as a means to promote recertification and quality of care, other countries, eg Belgium, France and the Netherlands, also incorporate peer review. In the UK the proposed revalidation scheme would include elements of relicensure through appraisal and feedback as well as physician recertification. Divergence between countries also exists in monitoring and enforcement. The European Commission should explore the implications for professional mobility of the diversity in the regulation of the medical profession.


Differentiation and Structure in Sulfolobus islandicus Rod-Shaped Virus Populations.
In the past decade, molecular surveys of viral diversity have revealed that viruses are the most diverse and abundant biological entities on Earth. In culture, however, most viral isolates that infect microbes are represented by a few variants isolated on type strains, limiting our ability to study how natural variation affects virus-host interactions in the laboratory. We screened a set of 137 hot spring samples for viruses that infect a geographically diverse panel of the hyperthemophilic crenarchaeon Sulfolobus islandicus. We isolated and characterized eight SIRVs (Sulfolobus islandicus rod-shaped viruses) from two different regions within Yellowstone National Park (USA). Comparative genomics revealed that all SIRV sequenced isolates share 30 core genes that represent 50-60% of the genome. The core genome phylogeny, as well as the distribution of variable genes (shared by some but not all SIRVs) and the signatures of host-virus interactions recorded on the CRISPR (clustered regularly interspaced short palindromic repeats) repeat-spacer arrays of S. islandicus hosts, identify different SIRV lineages, each associated with a different geographic location. Moreover, our studies reveal that SIRV core genes do not appear to be under diversifying selection and thus we predict that the abundant and diverse variable genes govern the coevolutionary arms race between SIRVs and their hosts.


Rib soft fixation produces better analgesic effects and is associated with cytokine changes within the spinal cord in a rat rib fracture model.
Traumatic rib fracture can cause severe pain and is usually associated with the depression of respiratory drive followed by severe respiratory complications. It is critical for patients with rib fracture to receive adequate analgesia. However, strong opioids and other analgesics often produces side effects and may even cause respiratory suppression. Meanwhile, rib fixation now has become a popular method for treating rib fracture patients. However, the actual molecular mechanism leading to its effectiveness as an analgesia has not been fully investigated, and the best analgesic method for its use in rib fracture patients has not yet been determined. We developed a new animal model for rib fracture and evaluated changes in pain severity after rib fixation. Our data indicated significantly better analgesic behavior if a soft string rib fixation is performed, which is associated with cytokine (interleukine-6 and interleukine-10) decreases in the spinal cord and co-localization with glia cells. Our results provided a treatment suggestion for rib fracture patients and the possible molecular mechanism for the analgesic effects. Further molecular mechanisms and the best therapeutic methods are still needed for this severe painful condition.


The face in the crowd revisited: a threat advantage with schematic stimuli.
Schematic threatening, friendly, and neutral faces were used to test the hypothesis that humans preferentially orient their attention toward threat. Using a visual search paradigm, participants searched for discrepant faces in matrices of otherwise identical faces. Across 5 experiments, results consistently showed faster and more accurate detection of threatening than friendly targets. The threat advantage was obvious regardless of whether the conditions favored parallel or serial search (i.e., involved neutral or emotional distractors), and it was valid for inverted faces. Threatening angry faces were more quickly and accurately detected than were other negative faces (sad or "scheming"), which suggests that the threat advantage can be attributed to threat rather than to the negative valence or the uniqueness of the target display.


Acute neuromedical and neurosurgical admissions. Standard and ultrafast MR imaging of the brain compared with cranial CT.
To evaluate the role of standard and ultrafast MR brain imaging and compare the information with CT. This was a prospective study of 114 patients with acute neurological symptoms and signs. CT brain examinations consisted of axial non-enhanced images. MR imaging consisted of standard spin-echo/fast spin-echo sequences and a series of rapid techniques including echoplanar and single shot fast spin-echo sequences. Using standard MR methods, 41% of the patients had all five sequences of good technical quality, while using ultrafast methods 81% of the patients had good technical quality examinations in all five sequences. In 3% of the cases, ischaemic stroke was incorrectly reported on CT. In 24% of the cases, MR gave extra diagnostic information not reported on CT and in a further 8%, one neuroradiologist reported the abnormality in agreement with the MR, whilst the other neuroradiologist reported the CT as normal. In 2 cases, subarachnoid haemorrhage was missed on MR. Subarachnoid haemorrhage was not shown on the ultrafast sequences. MR can be used to image acute neurological admissions with a high success rate, particularly using ultrafast methods. In many cases, MR provided extra information of direct clinical relevance not shown on CT.


Hospital consolidation and racial/income disparities in health insurance coverage.
Non-Hispanic whites are significantly more likely to have health insurance coverage than most racial/ethnic minorities, and this differential grew during the 1990s. Similarly, wealthier Americans are more likely to have health insurance than the poor, and this difference also grew over the 1990s. This paper examines the role of provider competition in increasing these disparities in insurance coverage. Over the 1990s, the hospital industry consolidated; we analyze the impact of this consolidation on health insurance take-up for different racial/ethnic minorities and income groups. We found that the hospital consolidation wave increased health insurance disparities along racial and income dimensions.


Glyceryl trinitrate-induced desensitization of guanylate cyclase in cultured rat lung fibroblasts.
Cultured rat lung fibroblasts were used to explore desensitization of guanylate cyclase to nitrovasodilators. The effect of pretreatment with glyceryl trinitrate (GTN) on the concentration-response curves of GTN and sodium nitroprusside (SNP) for cyclic GMP accumulation in intact cells and activation of guanylate cyclase in broken cell preparations was measured. Pretreatment of cells with 1 microM GTN for 3 h decreased cyclic GMP accumulation induced by GTN but had no effect on SNP-induced cyclic GMP accumulation. Pretreatment of cells with 100 microM GTN decreased the efficacy of GTN and SNP for cyclic GMP elevation by 89% and 40%, respectively. In contrast to results obtained with GTN, SNP slightly desensitized cyclic GMP accumulation induced by GTN and SNP. Pretreatment of cells with 100 nM atrial natriuretic peptide resulted in a 44% decrease in cyclic GMP accumulation induced by subsequent exposure to 10 nM atrial natriuretic peptide but had no effect on cyclic GMP elevation induced by nitrovasodilators. In experiments with crude preparations of soluble guanylate cyclase from cells pretreated with 1 mM GTN, activation of the enzyme by GTN and SNP was inhibited almost completely. Tolerance to GTN in intact cells could not be reversed by subsequent incubation with thiols such as cysteine, N-acetylcysteine or glutathione. However, overnight incubation of GTN-tolerant cells in media without added thiols resulted in complete recovery of responsiveness to GTN. Recovery of GTN-induced cyclic GMP accumulation was inhibited in a concentration-dependent manner by cycloheximide, suggesting that reversal of organic nitrate tolerance requires de novo synthesis of gyanylate cyclase.(ABSTRACT TRUNCATED AT 250 WORDS)


Vascular endothelial function and plasma homocysteine levels in Behcet's disease.
The purpose of the present study was to test endothelial function and to determine if plasma homocysteine levels are associated with endothelial injury in patients with Behcet's disease (BD). Flow-mediated dilation in patients with BD was smaller than that of control subjects (p = 0.001), and mean plasma homocysteine levels in patients with BD were significantly higher (p = 0.0001). On regression analysis, only mean plasma homocysteine concentration was independently related to flow-mediated dilation (F = 5.7, p = 0.001).


Healthcare Provider Perspectives on HIV Cure Research in Ghana.
Antiretroviral therapy (ART) has reduced mortality and improved life expectancy among HIV patients but does not provide a cure. Patients must remain on lifelong medications and deal with drug resistance and side effects. This underscores the need for HIV cure research. However, participation in HIV cure research has risks without guaranteed benefits. We determined what HIV healthcare providers know about HIV cure research trials, the risks involved, and what kind of cure interventions they are likely to recommend for their patients. We conducted in-depth qualitative interviews with 39 HIV care providers consisting of 12 physicians, 8 counsellors, 14 nurses, 2 pharmacists, 2 laboratory scientists, and 1 community advocate from three hospitals. Interviews were transcribed verbatim and coded, and thematic analysis was performed independently by two investigators. Participants were happy about the success of current treatments and hopeful that an HIV cure will be found in the near future, just as ART was discovered through research. They described cure as total eradication of the virus from the body and inability to test positive for HIV or transmit the virus. In terms of risk tolerance, respondents would recommend to their patients' studies with mild to moderate risks like what patients on antiretroviral therapy experience. Participants were reluctant to recommend treatment interruption to patients as part of a cure study and wished trials could be performed without stopping treatment. Healthcare providers categorically rejected death or permanent disability as an acceptable risk. The possibility of finding a cure that will benefit the individual or future generations was strong motivations for providers to recommend cure trials to their patients, as was transparency and adequate information on proposed trials. Overall, the participants were not actively seeking knowledge on cure research and lacked information on the various cure modalities under investigation. While hopeful for an HIV cure, healthcare providers in Ghana expect a cure to be definitive and pose minimal risk to their patients.


Personality changes and the role of counseling in the rehabilitation of patients with laryngeal cancer.
We conducted a study of 65 adults who had undergone laryngectomy for the treatment of laryngeal cancer. Our goal was to identify any abnormal personality traits in these patients and to assess the effect that psychological counseling might have on correcting these abnormalities and thereby improving postoperative voice rehabilitation. A Personality Trait Inventory (PTI) administered to all patients preoperatively identified 47 patients who had abnormal scores for at least three personality traits. These 47 patients were sent for preoperative psychological counseling, and 3 months following surgery, they underwent a follow-up PTI. At the follow-up assessment, 40 of these patients-32 men and 8 women-still registered abnormal scores for at least three traits. Half of the men and half of the women were randomized to receive 12 sessions of individualized psychological counseling over 6 months in addition to standard speech therapy (group I); the other patients received speech therapy only (group II). A follow-up PTI was administered at the completion of psychological counseling and/or speech therapy (postoperative month 9). Statistical analysis of the data was performed with the paired-samples test. Intragroup analysis of the follow-up PTI results revealed that both groups experienced a significant improvement in activity scores (p < 0.001) compared with their previous PTI results and that group I had significantly better scores for two other PTI traits-cyclothymia (mood swings) and depressive tendency (p < 0.05); neither group showed a significant improvement in dominance scores. Intergroup comparisons revealed that group I's activity and depressive tendency scores were significantly better than those of group II; there was no significant difference between the two groups in cyclothymia and dominance scores. Finally, comparison of results by sex, regardless of group, revealed that men had a significantly higher score for dominance and women had significantly higher scores for depressive tendency, emotional instability, introversion, and social desirability. We conclude that a preoperative personality analysis should be carried out in all patients scheduled for laryngectomy to identify those with personality problems that might benefit from psychological counseling. Correction of these problems should help in the physical, mental, vocational, and social rehabilitation of these patients.


Insulin resistance, metabolic syndrome and vascular diseases: update on mechanistic linkages.
Epidemiological associations are now well-established between insulin resistance, the metabolic syndrome and worsened cardiovascular outcomes. A direct role of insulin in vascular biology is also now broadly recognized. Specifically, insulin can directly stimulate the action of nitric oxide synthase, an effect that can be demonstrated both in vitro and in vivo. Insulin resistance, whether present endogenously or produced experimentally through exposure to fatty acids, glucosamine or tumour necrosis factor alpha, is associated with impaired endothelium-dependent vasodilation and, specifically, with impaired insulin-stimulated vasodilation. A number of potential molecular explanations for these observations are being pursued, with evidence to support a number of concurrent pathogenic mechanisms. These include insulin resistance-associated reductions in nitric oxide availability due to increases in oxidative stress (not requiring the presence of hyperglycemia), reduced availability of tetrahydrobiopterin and excess levels of asymmetrical dimethylarginine. A strong body of evidence also supports an excess of the vasoconstrictor endothelin, which may result directly from hyperinsulinemia and/or indirectly due to a loss of the suppressive effects of nitric oxide on endothelin production and action. The current leading edge of investigations into the association between insulin-resistant states and vascular dysfunction involves the expanding repertoire of adipocyte-derived hormones. Of these, particular interest has been focused on adiponectin, which has both vascular and metabolic actions, and may contribute importantly to the connection between metabolism and vascular function. Progress along these novel lines of investigation will continue to expand the understanding of the mechanisms linking insulin resistance, the metabolic syndrome and vascular disease.


Extending the field of play: Revealing the dynamics between sports, health and place.
Although the sub-discipline of sports geography has a long fifty-year history it has been, at best, a sporadic endeavor. Whilst clearly indicating the fundamental geographical qualities of sports, it has never really taking off to the extent that arguably it should have given sport's social profile and importance. In way of a solution this paper presents triple tracks, or ways forward, that might circumvent this academic shortfall and cover some of the missed ground. First, pursuing the health component of sport far more thoroughly and in its very broadest sense, including its public health adoption and specific wellbeing, fitness and aesthetic features. Second, defining sport broadly beyond elite forms to include a wide-range of physical and lifestyle activities that possess elements of personal or interpersonal competition. Third, complementing sports geography by developing 'spatial sports studies' as a more expansive interdisciplinary field of inquiry spanning the health and social sciences. Indeed, these tracks potentially unearth substantial new research capacity by together considering the dynamics between sports, health and place.


Protein immobilization on 3C-SiC (100) as a substrate for detecting the onset of acute myocardial infarction (AMI).
Silicon Carbide (SiC), has been shown to be a bio- and hema-compatible substrate that could potentially be used in biosensor applications. The development of a viable biorecognition interface using SiC as the substrate material for bio-detection is described. Surface modification with 3-aminopropyltriethoxysilane (APTES) and immobilization via covalent conjugation of antimyoglobin (anti-Myo) on the modified surfaces is achieved, which are initial steps for immunosensing based devices. Successful formation of APTES layers and antibody immobilization were identified with surface water contact angle (SWCA), X-ray photoelectron spectroscopy (XPS) and atomic force microscopy (AFM).


Internal translation of the connexin 43 transcript.
Connexin 43 (Cx43), the most widely expressed gap junction protein, is associated with a number of physiological and pathological conditions. Many functions of Cx43 have been shown to be independent of gap junction formation and only require the expression of Cx43 C-terminal fragments. Recent evidence demonstrated that naturally occurring C-terminal isoforms can be generated via internal translation. Here, we confirm that C-terminal domains of Cx43, particularly the major 20-kDa isoform, can be independently generated and regulated by internal translation of the same single GJA1 gene transcript that encodes full-length Cx43. Through direct RNA transfection experiments, we provide evidence that internal translation is not due to a bona fide cap-independent IRES-mediated mechanism, as upstream ribosomal scanning or translation is required. In addition to the mTOR pathway, we show for the first time, using both inhibitors and cells from knockout mice, that the Mnk1/2 pathway regulates the translation of the main 20-kDa isoform. Internal translation of the Cx43 transcript occurs but is not cap-independent and requires translation upstream of the internal start codon. In addition to the PI3K/AKT/mTOR pathway, the major 20-kDa isoform is regulated by the Mnk1/2 pathway. Our results have major implications for past and future studies describing gap junction-independent functions of Cx43 in cancer and other pathological conditions. This study provides further clues to the signalling pathways that regulate internal mRNA translation, an emerging mechanism that allows for increased protein diversity and functional complexity from a single mRNA transcript.


Gene therapy for gliomas: p53 and E2F-1 proteins and the target of apoptosis.
Current therapy for glioma is suboptimal. The transfer of apoptosis genes to tumors constitutes one of the most promising strategies for cancer gene therapy. We have previously shown that massive apoptosis occurs when wild-type p53 or E2F-1 expression is induced in glioma. However, the mechanism of action and the efficiency in inducing apoptosis of these two proteins are not similar. Adenovirus-mediated p53 gene transfer is ineffective in causing apoptosis in glioma cells that retain wild-type p53 genotype or overexpress the p21 protein. The p16/Rb/E2F pathway is the most frequent target of genetic alterations in gliomas, and therefore constitutes a suitable target for gene therapy strategies. However, the transfer of either the p16 or Rb gene to glioma cells results in cytostatic effect. The E2F-1 protein is able to induce generalized apoptosis in gliomas independently of the p53, p16 or Rb status. In addition, p21- or p16-mediated growth arrest did not protect glioma cells from E2F-1-mediated apoptosis. The apoptotic molecule bax is induced in p53-mediated apoptosis, but bax is not induced in E2F-1-mediated apoptosis in glioma cells. Careful selection of patients may be necessary before designing therapeutic strategies using either p53 or E2F-1 as a therapeutic tools for glioma patients.


Cell-mediated immunity in chronic myelocytic leukemia.
14 patients with chronic myelocytic leukemia were evaluated immunologically; no difference was found in mean lymphocyte percentage and absolute number between patients and healthy subjects. 4 cases (28.5%) showed decreased percentage of T lymphocytes, while only 2 cases (14.2%) had decreased absolute T lymphocyte values. PHA transformation was decreased in 57% of the patients. Spontaneous transformation in the short-term cultures exceeded the normal range in 65% of the cases. All patients skin tested were found to be reactive. Most of the patients had defective cellular immune response in vitro, probably related with a qualitative defect in T lymphocyte subpopulations. It cannot be completely excluded that part of the observed lymphocyte depression was due to the busulfan.


Regulation of intestinal phosphate transport. II. Metabolic acidosis stimulates Na(+)-dependent phosphate absorption and expression of the Na(+)-P(i) cotransporter NaPi-IIb in small intestine.
During metabolic acidosis, P(i) serves as an important buffer to remove protons from the body. P(i) is released from bone together with carbonate buffering protons in blood. In addition, in the kidney, the fractional excretion of phosphate is increased allowing for the excretion of more acid equivalents in urine. The role of intestinal P(i) absorption in providing P(i) to buffer protons and compensating for loss from bone during metabolic acidosis has not been clarified yet. Inducing metabolic acidosis (NH(4)Cl in drinking water) for 2 or 7 days in mice increased urinary fractional P(i) excretion twofold, whereas serum P(i) levels were not altered. Na(+)-dependent P(i) transport in the small intestine, however, was stimulated from 1.89 +/- 3.22 to 40.72 +/- 11.98 pmol/mg protein (2 days of NH(4)Cl) in brush-border membrane vesicles prepared from total small intestine. Similarly, the protein abundance of the Na(+)-dependent phosphate cotransporter NaPi-IIb in the brush-border membrane was increased 5.3-fold, whereas mRNA levels remained stable. According to immunohistochemistry and real-time PCR NaPi-IIb expression was found to be mainly confined to the ileum in the small intestine, and this distribution was not altered during metabolic acidosis. These results suggest that the stimulation of intestinal P(i) absorption during metabolic acidosis may contribute to the buffering of acid equivalents by providing phosphate and may also help to prevent excessive liberation of phosphate from bone.


The role of cysteine oxidation in DJ-1 function and dysfunction.
DJ-1 is a member of the large and functionally diverse DJ-1/PfpI superfamily and has homologs in nearly all organisms. Because of its connection to parkinsonism and cancer, human DJ-1 has been intensely studied for over a decade. The current view is that DJ-1 is a multifunctional oxidative stress response protein that defends cells against reactive oxygen species and mitochondrial damage, although the details of its biochemical function remain unclear. A conserved cysteine residue in DJ-1 (Cys106) is both functionally essential and subject to oxidation to the cysteine-sulfinate and cysteine-sulfonate. Consequently, the oxidative modification of Cys106 has been proposed to allow DJ-1 to act as a sensor of cellular redox homeostasis and to participate in cytoprotective signaling pathways in the cell. This review explores the current evidence for the role of cysteine oxidation in DJ-1 function, with emphasis on emerging models for how oxidative modification may regulate DJ-1's protective function and also contribute to dysfunction and disease.


Mechanisms for the regulation of state changes in the central nervous system: an introduction.
Current work on central nervous system (CNS) mechanisms underlying behavior has expanded from consideration of specific sensory codes or motor controls to the analyses of global CNS states. These include states of arousal, alertness, attention, emotional states regarding emotion and motivation, and states of addiction, which carry great importance for medicine and public health. In this brief introduction, orderly neuroanatomical concepts of forebrain pathways regulating motivated behaviors are presented. Neuropeptides often coordinate large sets of responses associated with an individual behavioral state. Here, we emphasize some of the central roles for opioid peptides. We also mention a few outstanding unanswered questions related to this area of neuroscience.


Cardio-metabolic disturbances are more correlated with waist-hip ratio (WHR) than body mass index (BMI) in patients with coronary vascular disease.
To evaluate the correlation of body mass index, waist circumference, hip circumference and waist-hip ratio with coronary vascular diseases in patients with ischaemic heart disease. The cross-sectional study was conducted at Al Yarmouk Teaching Hospital, Baghdad, Iraq, from March to October, 2016, and comprised patients with ischaemic heart disease. Biochemical parameters measured following overnight fasting included fasting blood glucose, total cholesterol, triglyceride and high density lipoprotein and low density lipoprotein. Anthropometric measurements included height, weight, body mass index, waist circumference, hip circumference and waist-hip ratio. Also measured were blood pressure and electrocardiography reading. Data was analysed using SPSS 21. Of the 100 patients, 59(59%) were males with a mean age of 60.7}7.27 years, and 41(41%) were females with a mean age of 59.4}8.8 (p>0.05). BMI values were also non-significant between the genders (p>0.05). Waist-hip ratio and hypertension were high in males compared to females (p<0.05), while coronary vascular disease was high in females compared to males(p<0.05).There was non-significant difference in terms of fasting blood glucose, high density lipoprotein and uric acid (p>0.05), But there was significant difference in total cholesterol, triglycerides and low density lipoprotein(p<0.05).Waist-hip ratio was more significantly correlated than body mass index with all metabolic and cardiovascular disorders (p<0.05), while high body mass index was correlated only with hypertension and diabetes. Waist-hip ratio was found to be more correlated with coronary vascular disease and cardio-metabolic profile than body mass index in patients with ischaemic heart disease.


Health Effects of PCBs in Residences and Schools (HESPERUS): PCB - health Cohort Profile.
Polychlorinated-biphenyls (PCBs) were introduced in the late 1920s and used until the 1970s when they were banned in most countries due to evidence of environmental build-up and possible adverse health effects. However they still persist in the environment, indoors and in humans. Indoor air in contaminated buildings may confer airborne exposure markedly above background regional PCB levels. To date, no epidemiological studies have assessed the health effects from exposure to semi-volatile PCBs in the indoor environment. Indoor air PCBs are generally less chlorinated than PCBs that are absorbed via the diet, or via past occupational exposure; therefore their health effects require separate risk assessment. Two separate cohorts of individuals who have either attended schools (n = 66,769; 26% exposed) or lived in apartment buildings (n = 37,185; 19% exposed), where indoor air PCB concentrations have been measured were created. An individual estimate of long-term airborne PCB exposure was assigned based on measurements. The cohorts will be linked to eight different national data sources on mortality, school records, residential history, socioeconomic status, and chronic disease and reproductive outcomes. The linking of indoor air exposures with health outcomes provides a dataset unprecedented worldwide. We describe a project, called HESPERUS (Health Effects of PCBs in Residences and Schools), which will be the first study of the long term health effects of the lower-chlorinated, semi-volatile PCBs in the indoor environment.


Binding action and emotion in first-episode schizophrenia.
Several components of social cognition are compromised in schizophrenia (SCZ) from the early stage of the illness. In this study we first investigated whether mirror neuron-driven embodied simulation (mnES) is altered in first-episode SCZ. Second, we tested whether emotional cues impact on the mnES in SCZ patients. Twenty-two SCZ patients and 22 healthy controls (HCs) observed goal-related actions in either a neutral or emotional context during functional magnetic resonance imaging scanning. Observation of neutral action elicited a lower activity in the frontoparietal network in SCZ patients, as compared to HCs. Particularly, activation in the left inferior parietal lobule in response to the same condition negatively correlated with patients' self-experience disturbances. Moreover, observation of an action performed by an angry agent produced poorer neural activity in the right anterior insula in SCZ patients as compared to HCs. This difference was mostly due to the negative β-values shown by SCZ patients, which positively correlated with their empathy scores. No differences were found contingent upon the observation of an action performed by a happy agent. Our results show that emotional cues allow SCZ patients to partially recover mnES. However, their understanding of the emotional components of the actions of others will likely remain deficient.


Developing an Internship Preparedness Program for Final Year Medical Students.
This article was migrated. The article was marked as recommended. Introduction: Medical students undertake extensive training yet often feel they lack the practical non-medical skills required for successful transition to internship. While research provides evidence for student perceptions and experiences regarding internship, there is little information regarding how students can be 'taught' work-readiness through learning non-medical skills. Methods: By reducing cognitive load when structured using a flipped classroom method, active learning resources may provide an effective approach to prepare medical students to be work-ready interns. Using a blended instructional method, the University of Queensland's Rural Clinical School (UQRCS) integrated face-to-face and online learning, to develop an Intern Preparedness program. Discussion: The Intern Preparedness program promotes student interaction in a range of active learning tasks to improve learning and engagement in a difficult and often neglected area of professional training. The program focused on providing knowledge and skills to increase competency in non-medical skills including time management on the ward, patient-focused prioritisation of tasks, and clinical conversations with the healthcare team. Conclusion: This program has become an integral part of the student learning experiences at the UQRCS as it continues to elevate student preparedness for internship. The program has become a fundamentally important aspect of improving cognitive skills such as critical thinking and reasoning, as well as soft skills, which are all essential for successful transitions to internship. A very high uptake and completion of program activities provided further incentive for program developers to continue its improvements over time.


Recent and past musical activity predicts cognitive aging variability: direct comparison with general lifestyle activities.
Studies evaluating the impact of modifiable lifestyle factors on cognition offer potential insights into sources of cognitive aging variability. Recently, we reported an association between extent of musical instrumental practice throughout the life span (greater than 10 years) on preserved cognitive functioning in advanced age. These findings raise the question of whether there are training-induced brain changes in musicians that can transfer to non-musical cognitive abilities to allow for compensation of age-related cognitive declines. However, because of the relationship between engagement in general lifestyle activities and preserved cognition, it remains unclear whether these findings are specifically driven by musical training or the types of individuals likely to engage in greater activities in general. The current study controlled for general activity level in evaluating cognition between musicians and nomusicians. Also, the timing of engagement (age of acquisition, past versus recent) was assessed in predictive models of successful cognitive aging. Seventy age and education matched older musicians (>10 years) and non-musicians (ages 59-80) were evaluated on neuropsychological tests and general lifestyle activities. Musicians scored higher on tests of phonemic fluency, verbal working memory, verbal immediate recall, visuospatial judgment, and motor dexterity, but did not differ in other general leisure activities. Partition analyses were conducted on significant cognitive measures to determine aspects of musical training predictive of enhanced cognition. The first partition analysis revealed education best predicted visuospatial functions in musicians, followed by recent musical engagement which offset low education. In the second partition analysis, early age of musical acquisition (<9 years) predicted enhanced verbal working memory in musicians, while analyses for other measures were not predictive. Recent and past musical activity, but not general lifestyle activities, predicted variability across both verbal and visuospatial domains in aging. These findings are suggestive of different use-dependent adaptation periods depending on cognitive domain. Furthermore, they imply that early age of musical acquisition, sustained and maintained during advanced age, may enhance cognitive functions and buffer age and education influences.


A graph-based approach can improve keypoint detection of complex poses: a proof-of-concept on injury occurrences in alpine ski racing.
For most applications, 2D keypoint detection works well and offers a simple and fast tool to analyse human movements. However, there remain many situations where even the best state-of-the-art algorithms reach their limits and fail to detect human keypoints correctly. Such situations may occur especially when individual body parts are occluded, twisted, or when the whole person is flipped. Especially when analysing injuries in alpine ski racing, such twisted and rotated body positions occur frequently. To improve the detection of keypoints for this application, we developed a novel method that refines keypoint estimates by rotating the input videos. We select the best rotation for every frame with a graph-based global solver. Thereby, we improve keypoint detection of an arbitrary pose estimation algorithm, in particular for 'hard' keypoints. In the current proof-of-concept study, we show that our approach outperforms standard keypoint detection results in all categories and in all metrics, in injury-related out-of-balance and fall situations by a large margin as well as previous methods, in performance and robustness. The Injury Ski II dataset was made publicly available, aiming to facilitate the investigation of sports accidents based on computer vision in the future.


Proposed radiological criteria for pre-operative determination of resectability in peritoneal-based malignancies.
The selection of patients for cytoreductive surgery (CRS) and hyperthermic intra-peritoneal chemotherapy infusion (HIPEC) is important, and relies heavily on imaging. However, it has been reported that Computer Tomographic (CT) scans may only achieve a low sensitivity of 33% for peritoneal disease. We propose a set of radiological criteria for pre-operative determination of resectability of peritoneal disease in peritoneal-based malignancies and validate this in our cohort of patients. A retrospective review of all patients who underwent laparotomy with a view for CRS and HIPEC, at the National Cancer Centre Singapore from January 2000 to April 2010, was performed. Intra-operative Peritoneal Cancer Index (PCI) scores were recorded. The pre-operative imaging was reviewed with a senior radiologist who was blinded, and recorded the radiological PCI scores (CT-PCI) and eight additional CT prognostic factors (CT-PF). The CT-PCI and CT-PF scores were then compared with the intra-operative findings to determine the radiological accuracy. The scores and the individual prognostic factors were then evaluated for their predictive ability for unresectability. Comparison of the CT-PCI and PCI scores showed a concordance correlation coefficient at 0.52 (95% CI 0.34-0.7). Accuracy was increased with the addition CT-PF. The presence of omental caking and ascites were predictors of unresectability. We propose a scoring system which is able to predict for unresectable disease with a specificity of 80% and a sensitivity of 62%. With our proposed criteria, and scoring system, the selection of patients for CRS and HIPEC can be improved, and unnecessary exploratory operations avoided.


Integrated radiotherapy imaging system (IRIS): design considerations of tumour tracking with linac gantry-mounted diagnostic x-ray systems with flat-panel detectors.
The design of an integrated radiotherapy imaging system (IRIS), consisting of gantry mounted diagnostic (kV) x-ray tubes and fast read-out flat-panel amorphous-silicon detectors, has been studied. The system is meant to be capable of three main functions: radiographs for three-dimensional (3D) patient set-up, cone-beam CT and real-time tumour/marker tracking. The goal of the current study is to determine whether one source/panel pair is sufficient for real-time tumour/marker tracking and, if two are needed, the optimal position of each relative to other components and the isocentre. A single gantry-mounted source/imager pair is certainly capable of the first two of the three functions listed above and may also be useful for the third, if combined with prior knowledge of the target's trajectory. This would be necessary because only motion in two dimensions is visible with a single imager/source system. However, with previously collected information about the trajectory, the third coordinate may be derived from the other two with sufficient accuracy to facilitate tracking. This deduction of the third coordinate can only be made if the 3D tumour/marker trajectory is consistent from fraction to fraction. The feasibility of tumour tracking with one source/imager pair has been theoretically examined here using measured lung marker trajectory data for seven patients from multiple treatment fractions. The patients' selection criteria include minimum mean amplitudes of the tumour motions greater than 1 cm peak-to-peak. The marker trajectory for each patient was modelled using the first fraction data. Then for the rest of the data, marker positions were derived from the imager projections at various gantry angles and compared with the measured tumour positions. Our results show that, due to the three dimensionality and irregular trajectory characteristics of tumour motion, on a fraction-to-fraction basis, a 'monoscopic' system (single source/imager) is inadequate for consistent real-time tumour tracking, even with prior knowledge. We found that, among the seven patients studied with peak-to-peak marker motion greater than 1 cm, five cases have mean localization errors greater than 2 mm and two have mean errors greater than 3 mm. Because of this uncertainty associated with a monoscopic system, two source/imager pairs are necessary for robust 3D target localization. Dual orthogonal x-ray source/imager pairs mounted on the linac gantry are chosen for the IRIS. We further studied the placement of the x-ray sources/panel based on the geometric specifications of the Varian 21EX Clinac. The best configuration minimizes the localization error while maintaining a large field of view and avoiding collisions with the floor/ceiling or couch.


Prognostic role of N-Acetylgalactosaminyltransferase 10 in metastatic renal cell carcinoma.
A previous study demonstrated that GALNT10 affects the sensitivity of cancer cells to tyrosine kinase inhibitor (TKI) therapy. The aim of this study was to assess whether GALNT10 holds a prognostic role in metastatic renal cell carcinoma (mRCC) patients treated with TKI agents. GALNT10 had no statistical correlation with any other clinicopathological parameters except for route of gaining samples (P = 0.001) and Heng's risk stratification (P = 0.011). Patients with high level of GALNT10 had significantly shorter overall survival (OS) (P < 0.001) and progression-free survival (PFS) (P = 0.002). Importantly, this relationship existed in OS and PFS analyses in sunitinib-treated patients and in OS analyses in sorafenib-treated patients (P = 0.024). In contrast to sorafenib group, percentage of partial response (PR) and stable disease (SD) were higher in sunitinib group, while percentage of progression disease (PD) was much lower. Univariate and multivariate analyses identified that GALNT10 was an independent prognostic factor for OS (HR = 1.938, P = 0.014), not for PFS (HR = 1.532, P = 0.065), in mRCC. Incorporating it into Heng's risk model could sharpen its efficacy in distinguishing patients with potential higher risk. We retrospectively enrolled 138 mRCC patients treated with sunitinib or sorafenib at Zhongshan Hospital, Shanghai, China. A total of 111 valid cases were finally applied for analyses. These findings suggest that GALNT10 could be applied as a prognostic marker for OS in mRCC patients.


Two tales of Annexin A2 knock-down: One of compensatory effects by antisense RNA and another of a highly active hairpin ribozyme.
Besides altering its own expression during cell transformation, Annexin A2 is upregulated during the progression of many cancer types and also plays key roles during viral infection and multiplication. Consequently, there has been great interest in Annexin A2 as a potential drug target. The successful design of efficient in vivo delivery systems constitutes an obstacle in full exploitation of antisense and RNA-cleaving technologies for the knock-down of specific targets. Efficiency is dependent on the method of delivery and accessibility of the target. Here, hairpin ribozymes and an antisense RNA against rat annexin A2 mRNA were tested for their efficiencies in a T7-driven coupled transcription/translation system. The most efficient ribozyme and antisense RNA were subsequently inserted into a retroviral vector under the control of a tRNA promoter, in a cassette inserted between retroviral Long Terminal Repeats for stable insertion into host DNA. The Phoenix package system based on defective retroviruses was used for virus-mediated gene transfer into PC12 cells. Cells infected with the ribozyme-containing particles died shortly after infection. However, the same ribozyme showed a very high catalytic effect in vitro in cell lysates, explained by its loose hinge helix 2 region. This principle can be transferred to other ribozymes, such as those designed to cleave the guide RNA in the CRISPR/Cas9 technology, as well as to target specific viral RNAs. Interestingly, efficient down-regulation of the expression of Annexin A2 by the antisense RNA resulted in up-regulation of Annexin A7 as a compensatory effect after several cell passages. Indeed, compensatory effects have previously been observed during gene knock-out, but not during knock-down of protein expression. This highlights the problems in interpreting the phenotypic effects of knocking down the expression of a protein. In addition, these data are highly relevant when considering the effects of the CRISPR/Cas9 approach.


A comparison of the economics of xenon 127, xenon 133 and krypton 81m for routine ventilation imaging of the lungs.
We have compared the cost of providing routine lung ventilation scintigraphy using 127Xe with other radioactive gases in 100 patients. The physical properties of 127Xe permit a logical imaging sequence where a ventilation study is only carried out if indicated by perfusion scintigraphy which is performed first. With 133Xe, all patients must be ventilated prospectively, or a preselection carried out based on radiographic appearances at the time of imaging. This results in a greater number of ventilation studies than with 127Xe. Despite the greater cost per study of 127Xe, the overall cost of providing a routine diagnostic service with this gas is no more than that of using 133Xe in selected patients. The cost of ventilating all patients prospectively with 133Xe is considerably greater than using 127Xe only when indicated by abnormal perfusion images. If ventilation imaging is to be available at all times, either isotope of xenon costs very much less than 81Krm. We conclude that 127Xe is the radiopharmaceutical of choice for routine lung ventilation scintigraphy.


[Species composition and microbial contamination of atmospheric humidity condensate and potable water from the Mir water supply systems during Mir main missions 4 through 27].
Analyzed were quantitative and qualitative characteristics, and processes of formation and transformation of microflora in the atmospheric humidity condensate (AHC) and potable water (PW) regenerated from the condensate by the long-operating system (SRV-K) aboard space station Mir. The paper presents data on species composition of microflora of AHC, and PW regenerated by SRV-K in the period from 1989 through to 1999. The following microbial species were identified in AHC: Alcaligenes (14.8%), Bacillus (3.7%), Citrobacter (7.4%), Clostridium (11.1%), Enterobacter (7.4%), Proteus (7.4%), Pseudomonas (18.5%), and Staphylococcus (100%). There were two PW cocks in SRV-K--"hot" and "cold". "Hot" PW microflora included Alcaligenes (15%), Bacillus (5%), Citrobacter (20%), Clostridium (5%), Enterobacter (15%), Proteus (10%), Pseudomonas (15%), and Staphylococcus (75%). "Cold" PW microflora included Aeromonas (14.3%), Alcaligenes (21.4%), Bacillus (7.1%), Citrobacter (7.1%), Clostridium (7.1%), Enterobacter (7.1%), Moraxella (7.1%), Pseudomonas (7.1%), and Staphylococcus (78.5%). Microbial content averaged 8.9 x 10(2) +/- 1.3 (0.01-4) x 10(3) CFU/ml in condensate and 1.5 +/- 0.1 (0-3.0) CFU/ml in regenerated potable water.


Rad51 inhibits translocation formation by non-conservative homologous recombination in Saccharomyces cerevisiae.
Chromosomal translocations are a primary biological response to ionizing radiation (IR) exposure, and are likely to result from the inappropriate repair of the DNA double-strand breaks (DSBs) that are created. An abundance of repetitive sequences in eukaryotic genomes provides ample opportunity for such breaks to be repaired by homologous recombination (HR) between non-allelic repeats. Interestingly, in the budding yeast, Saccharomyces cerevisiae the central strand exchange protein, Rad51 that is required for DSB repair by gene conversion between unlinked repeats that conserves genomic structure also suppresses translocation formation by several HR mechanisms. In particular, Rad51 suppresses translocation formation by single-strand annealing (SSA), perhaps the most efficient mechanism for translocation formation by HR in both yeast and mammalian cells. Further, the enhanced translocation formation that emerges in the absence of Rad51 displays a distinct pattern of genetic control, suggesting that this occurs by a separate mechanism. Since hypomorphic mutations in RAD51 in mammalian cells also reduce DSB repair by conservative gene conversion and stimulate non-conservative repair by SSA, this mechanism may also operate in humans and, perhaps contribute to the genome instability that propels the development of cancer.


School-Based Physical Therapists' Experiences and Perceptions of How Student Goals Influence Services and Outcomes.
Aims: Individualized goals are the foundation for physical therapy services and outcomes. This research describes school-based physical therapists' (PTs) experiences and perceptions of how student goals impact services and outcomes. Methods: Twenty school-based PTs participated in one of five semi-structured focus groups on goal development and use. Therapists were recruited from 113 therapists who participated in a study of school-based physical therapy outcomes. Two researchers conducted thematic analysis of written transcriptions of audio recordings to identify qualitative themes; a third researcher reviewed the analysis. Results: Four themes emerged related to how goals impact services: (1) the nature of services, (2) intervention strategies, (3) teaming, and (4) flexibility of services. Three themes emerged related to how goals impact outcomes: (1) natural linkages among goals, services, and outcomes; (2) goals impact teaming to achieve outcomes; and (3) specifics of the goal matter. Therapists also reported a range of student and environmental factors that impact services and outcomes. Conclusions: Therapists perceive that goals influence services and outcomes in complex ways, especially due to the flexibility and individualization needed in school-based practice. This study helps school-based PTs understand and reflect on how individualized goals influence services and optimize student outcomes.


[Wallenberg syndrome: magnetic imaging findings and clinical correlation].
Wallenberg's syndrome is one of the most common clinically recognized conditions due to brain stem infarct, which can nowadays be identified by modern neuro-imaging techniques. We describe a patient complaining of miosis, dysphonia, and dysphagia followed by ataxia. An MRI evaluation was performed including diffusion-weighted imaging, apparent diffusion coefficient, T2-weighted images, fluid attenuated inversion recovery (FLAIR) and perfusion. A brief discussion of imaging findings is presented as well as a clinical correlation of the symptoms with the anatomic location of the lesion. This case report emphasizes the importance of imaging findings and their clinical correlation with neurological examination.


Economic and health effect of full adherence to controller therapy in adults with uncontrolled asthma: a simulation study.
Adherence to evidence-based controller treatments for asthma is disappointingly low in many jurisdictions. Quantifying the burden associated with suboptimal adherence in patients with uncontrolled asthma will help establish the priorities for policymakers. We sought to quantify the benefits in the United States of improving adherence to controller therapies in adults with uncontrolled asthma in terms of health care costs and quality-adjusted life years (QALYs). A Markov model of asthma was created to simulate the effect of treatment with controller medications on asthma control and exacerbations over a 10-year time horizon. Health care costs and QALYs associated with the current level of adherence (status quo) were compared with a hypothetical scenario in which each patient with uncontrolled asthma at baseline will be fully adherent to an evidence-based controller therapy (the full-adherence scenario). We also evaluated the cost-effectiveness of adherence interventions as a function of their costs and improvement in the adherence. The status quo level of asthma management was associated with $2,786 costs and 7.55 QALYs over 10 years, whereas the corresponding values for the full-adherence scenario were $5,973 and 7.68, respectively. Consequently, the incremental cost-effectiveness ratio of the full-adherence versus the status quo was $24,515/QALY. To be cost-effective, a program that improves adherence by 50% should cost less than $130 ($450) per person annually at a willingness-to-pay value of $50,000/QALY ($100,000/QALY). Inclusion of productivity loss in the analysis resulted in the full-adherence scenario being cost-saving. Considering the extent of suboptimal adherence, our study shows that attempts in improving adherence to evidence-based therapies in patients with uncontrolled asthma can be associated with significant return on investment.


Therapeutic Plasmapheresis: Seven Year Experience of an Intensive Care Unit in Portugal.
Therapeutic plasmapheresis is a therapeutic procedure in which the patient's blood is passed through a medical device which separates out plasma from other components of blood. The plasma is removed and replaced with a replacement solution. Studies on the use of plasmapheresis in critically ill patients are scarce. The aim of this study was to review all therapeutic plasmapheresis sessions carried out in the Hospital Beatriz Ângelo intensive care unit. An observational retrospective study was conducted between April 2012 and March 2019. All patients who underwent therapeutic plasmapheresis in the intensive care unit were included, and plasmapheresis sessions held outside the intensive care unit were excluded. Of 46 patients, 63% were men (n = 29), with a median age of 53 years. The most frequent diagnoses were hypertriglyceridemia-induced pancreatitis, vasculitis, autoimmune haemolytic anaemia, and atypical haemolytic-uremic syndrome. A total of 198 plasmapheresis sessions were carried out in the intensive care unit. Most of the used replacement solutions were fresh frozen plasma (34.4%), albumin/crystalloid (24.2%), and albumin/fresh frozen plasma (19.2%). The most common complications were hydroelectrolytic changes (84; 42.4%) and coagulation disorders/thrombocytopenia (65; 32.8%). There was no need to interrupt any plasmapheresis session due to complications related to the patient. Therapeutic plasmapheresis is an urgent procedure that can reduce morbidity and mortality in critically ill patients. This justifies that 37% of patients started the technique before the diagnostic confirmation. The indications for plasmapheresis and the choice of replacement solution were in agreement with the guidelines. Despite the risk of bleeding, no haemorrhagic complications were recorded. Therapeutic plasmapheresis is a complex technique that requires specific training. The indications are diverse, and some are not consensual. Complications were frequent, but they did not increase morbidity.